Among the most common and debilitating neurological complications of HIV infection is HIV associated dementia (HAD) or AIDS dementia complex (ADC). The exact pathogenesis of this disorder remains a conundrum, but trafficking of HIV-infected peripheral macrophages across the blood-brain barrier (BBB) appears to be an important route of entry of HIV, and the rate at which this occurs may be a determinant of HAD onset and/or progression. BBB breakdown is known to increase the rate of macrophage trafficking into CNS, and there is evidence for microvascular abnormalities, including increased regional blood volume (RCBV) and BBB disruption in HIV seropositive and particularly in HAD patients. Indeed preliminary results suggest that the severity of these microvascular changes is correlated with the severity of HAD. Zidovudine monotherapy and, more recently, highly active anti-retroviral therapy (HAART) may reduce the incidence of HAD. Furthermore, zidovudine or HAART may arrest or even reverse the dementing process, at least temporarily, in many but not all patients. The means by which HAART might slow the progression of HAD is unclear, but may include reduced trafficking of infected and/or activated macrophage into the CNS both as a result of a reduced serum viral load, and also by reversing the damage to the BBB. In this study employing patients with HAD of varying severity, carefully studied by clinical examination, neuropsychological test battery, and contrast-enhanced magnetic resonance imaging (MRI), we propose to test the over-arching hypothesis that disruption of cerebral microvascular integrity is a key event in progression to HAD, (with the severity of HAD correlated with the degree of microvascular disruption) and that therapies which reverse these microvascular defects lead to improvement in RAD.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
1R01MH063040-01
Application #
6316329
Study Section
Special Emphasis Panel (ZMH1-NRB-A (02))
Program Officer
Rausch, Dianne M
Project Start
2000-09-30
Project End
2005-08-31
Budget Start
2000-09-30
Budget End
2001-08-31
Support Year
1
Fiscal Year
2000
Total Cost
$253,750
Indirect Cost
Name
University of Kentucky
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
832127323
City
Lexington
State
KY
Country
United States
Zip Code
40506
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Berger, Joseph R; Avison, Malcolm (2004) The blood brain barrier in HIV infection. Front Biosci 9:2680-5